It is one of humanity’s biggest mysteries: how do the cells in a fertilized embryo manage to divide and differentiate to form the intricate and complex architecture of the human brain? Neuroscientists across the globe have lauded the Human Connectome Project as a game changer in understanding how the brain develops.

“We now have the tools to begin to map out the wiring and functional connections in the brain that weren’t really possible before,” says Thomas Insel, director of the National Institute of Mental Health (NIMH) and a member of the Dana Alliance for Brain Initiatives. “By looking at the way connections are made as the brain develops, it provides us an opportunity to find out how the variation seen in the structural and functional anatomy related to major psychiatric disorders may occur.”

Research studies both within the Connectome consortium and beyond are now offering scientists new insight into the causes of disorders like schizophrenia, bipolar disorder, and depression—and showing that the roots of psychiatric disease go deeper, and start growing earlier, than previously imagined.

Schizophrenia as “derailed” brain development

Several studies in the past year suggest that schizophrenia is linked to progressive growth that results in structural abnormalities in the brain. Andrew McIntosh, a researcher at the University of Edinburgh’s Centre for Clinical Brain Sciences, and colleagues followed people with a high genetic risk for schizophrenia for 10 years using cognitive tests and brain scans to try to predict who might later develop the disorders. The group found that individuals who would later become psychotic showed reductions in brain volume in several areas of the brain. The results were published in the May 15, 2011, issue of Biological Psychiatry.

“There’s been evidence that changes to the prefrontal lobe may be predictive of schizophrenia. We found that those who became unwell later had reductions in the size of the prefrontal lobe as well as altered brain function in the region,” he said. “We also saw changes in the functioning of the temporal and parietal lobes which seem also to be involved with the development of schizophrenia.”

McIntosh argues that these brain changes occur long before a person's first psychotic episode—and if recognized then would offer an opportunity to intervene early and perhaps stop schizophrenia before it develops.

“There seem to be problems with brain development that go back to the womb, presumably caused in large part by genes,” says McIntosh. “It’s something you can see manifested by differences in brain shape and size, different palm ridges and patterns in the hand, and also in behavioral problems in children. Many of these processes seem to lie dormant until adolescence and early adulthood, when the symptoms of schizophrenia begin to emerge. But we believe those symptoms, that deterioration of function in adolescence and early adulthood, is caused at least partly by developmental problems that took place many, many years earlier.”

A question of timing

While animal research has helped show us how genes help the brain develop in mammals, it can be difficult to find the right tie-ins to psychiatric disorders—many of which are uniquely human.

“So much of our understanding of brain development is extrapolated from animal models and, to date, we don’t really know all that much about how genes govern human brain development. We’re looking at how genes help neurons acquire their identities and forge connections,” says Nenad Sestan, a neuroscientist at Yale University’s Kavli Institute for Neuroscience. “And as part of that, we’re also interested in how these developmental processes have changed during evolution and in disease states.”

In a study published in the Oct. 27, 2011, issue of Nature, Sestan and colleagues tracked the genes involved in human brain development, as well as when and where in the brain they were expressed. The group demonstrated that most of the genes currently known to be associated with psychiatric disorders are expressed in utero, long, long before any related behavioral symptoms develop.

“When we think about brain development in an evolutionary context, we know that humans have complex and intricately wired neural circuits in the cerebral cortex. It is the emergence of these incredible circuits that give us our remarkable cognitive and motor abilities,” he says. “But, at the same time, the emergence of these circuits, and the development involved in all this extra wiring, may have also increased our susceptibility to psychiatric disorders.”

Epigenetics and sex differences

While “genes of interest” have been identified in many psychiatric disorders, they do not work in a vacuum. Work in the field of epigenetics is demonstrating a variety of environmental variables that can speed up or slow down the expression of these genes. Geert de Vries, a researcher at the University of Massachusetts Amherst who studies the development of sex differences in the brain, argues that sex steroids like estrogen and testosterone are uniquely poised to affect genes—and may play a role in the sex differences observed in the prevalence ratios of psychiatric disorders.

“You see that females are more likely to develop depression, males are more likely to get autism or schizophrenia. Sex steroids set the stage for many, many changes in brain development, some of which are permanent, and many of which are sex-specific,” says de Vries. “It is quite likely that the factors that change the potential of getting a certain disorder might have also changed the course of normal sexual differentiation in the brain.”

De Vries argues that many key brain circuits show sexual differentiation during development. And given that animal studies shown that prenatal stress can result in significant differences in an animal’s demeanor and behavior, he believes it’s not a reach to believe that interrupting these natural sex differences may be linked to those later sex-specific psychiatric issues. “We know that stress can somehow interact with the process of sexual differentiation in the brain,” he says. “People are now very interested in seeing whether something like early stress can increase aggressive behaviors or even disorders like schizophrenia. If we can identify a specific epigenetic modification like that, we can then perhaps find a way to reverse it before a person even shows the behavioral symptoms of a disorder.”

Looking to the future

Although many are hopeful that the Connectome project will provide some much-needed data on brain development, it is clear that it cannot provide the entire picture when it comes to better understanding psychiatric disorders. McIntosh is calling for integration of information from all levels of neuroscience: from genome to epigenome to cell to neurocircuit to behavior.

“Now that we can understand what it is that we’re looking at with the [brain] scanner, we have an idea of where to start looking for cellular and molecular changes,” says McIntosh. “We think [schizophrenia] might be a reduction in cell size or a reduction in the completion of the brain. The obvious next step is to look at these regions at the cellular level and learn more about what might be causing these structural and functional changes, as well as back to the genetics to see how some of the genes that have been implicated in schizophrenia fit into the puzzle. By tying all of the pieces together, it may be possible to find processes that are amenable to prevention or treatment.”

Despite the newness of this work, Insel hopes that it will offer scientists and clinicians a new way to think about both the prevention and treatment of these debilitating disorders.

“Often, the behavior and cognitive changes that we’ve previously used as the diagnostic test for an illness are very late events,” he says. “Think about Parkinson’s disease. You don’t develop the symptoms of Parkinson’s until you’ve lost about 80 percent of your dopamine cells. That’s very late in the game. It may be the same for other psychiatric disorders like schizophrenia, autism, or depression. So the ability to study these brain circuits and processes could offer an opportunity to not only detect these disorders much earlier but actually redefine them so we aren’t limited to just trying to treat late stage events. That’s huge.”